Broad Spectrum Corona Virus Protease Inhibitor

Onaviruses betacoronaviruses and enteroviruses we pursued a structure-based design of. Coxsackievirus B3 3C pro.

Plos Pathogens Reversal Of The Progression Of Fatal Coronavirus Infection In Cats By A Broad Spectrum Coronavirus Protease Inhibitor

This review will systematically describe potential broad-spectrum coronavirus fusion inhibitors including antibodies protease inhibitors and peptide fusion inhibitors along with a discussion of their advantages and disadvantages.

Broad spectrum corona virus protease inhibitor. The main protease Mpro of SARS-CoV-2 is a key antiviral drug target. GC376 is a broad-spectrum antiviral drug that inhibits M pro of several viruses including the coronaviruses like feline coronavirus porcine epidemic diarrhoea virus severe acute respiratory syndrome coronavirus Middle East respiratory syndrome coronavirus ferret and mink coronavirus. Previously we have reported the inhibitors that target 3C-like protease 3CLpro with broad-spectrum activity against important human and animal coronaviruses.

While most Mpro inhibitors have a g-lactam glutamine surrogate at the P1 position we recently found that several Mpro inhibitors have hydrophobic moieties at the P1 site including calpain inhibitors II and XII which are also active against human cathepsin L a host protease that is important for viral entry. We have previously reported the efficacy of a protease inhibitor in cats with FIP demonstrating that a virally encoded 3C-like protease 3CLpro is a valid target for antiviral drug development for coronavirus infections. Since both GC373 and GC376 have already been successfully used in treating animal coronavirus infection they can be considered as strong drug candidates for COVID-19 in humans.

Further M pro is highly conserved among various CoVs and a mutation in M pro is often lethal to the virus. The X-ray structures of the unliganded SARS-CoV-2 protease 3CLpro and its complex with an a-ketoamide inhibitor provides a basis for design of a-ketoamide inhibitors 6 for a treatment of SARS-CoV-2 infection. In order to obtain near-equipotent broad-spectrum antivirals against alphacor-.

HCoV-229E M pro refs. The protease 3CLpro is a potential drug target for coronavirus infections due to its essential role in processing the polyproteins that are translated from the viral RNA. Due to the conservation of structure and catalytic mechanism of coronavirus main protease repurposition of GC376 against SARS-CoV-2 may be an effective way for the treatment.

K11777 is already in advanced stages of development for a number of parasitic diseases such as Chagas disease and has. And closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. Specific Inhibitors of Mpro As a result several potent inhibitors of this enzyme have been designed all of which contain a glutamine-mimetic substitution of 2-pyrrolidone at P1.

SARS-CoV M pro refs. The active site cysteine and histidine are shown in the. Kim Y 1 Shivanna V 2 Narayanan S 2 Prior AM 3 Weerasekara S 3 Hua DH 3 Kankanamalage AC 4 Groutas WC 4 Chang KO 2.

Peptidomimetic a-ketoamides as inhibitors of main and 3C proteases. Feline infectious peritonitis a fatal coronavirus infection in cats was successfully treated previously with a prodrug GC376 a dipeptide-based protease inhibitor. Other research groups have also reported the discovery of antiviral drugs using this drug-repurposing approach which included a number of broad-spectrum inhibitors of HCoVs lycorine emetine.

Li Z Sakamuru S Huang R et al. Cocrystal Pharma a clinical-stage biotechnology company recently announced that a series of broad-spectrum protease inhibitors developed at K-State and licensed through K-State Innovation Partners in April 2020 has been selected as a preclinical lead compound for further development. Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease Antiviral Res.

Six crystal structures of. Previous studies show that GC376 a broad-spectrum dipeptidyl M pro inhibitor efficiently blocks the proliferation of many animal and human coronaviruses including SARS-CoV Middle East respiratory syndrome coronavirus MERS-CoV porcine epidemic diarrhea virus PEDV and feline infectious peritonitis virus FIPV. As of 2020 GC376 is being investigated as treatment for COVID-19.

Anivive licensed the exclusive worldwide patent rights to GC376 from Kansas State University. We have developed broad-spectrum inhibitors of an array of viruses including coronaviruses and noroviruses 1118 that use 3CLpro for viral replication and picornaviruses that use 3C protease. Experimental FIP is 100 fatal once certain clinical and laboratory signs become apparent.

Protease inhibitors targeting coronavirus and filovirus entry Antiviral Res. See also ref. An attractive therapeutic target for CoVs is the main protease M pro or 3-chymotrypsin-like cysteine protease 3CL pro as this enzyme plays a key role in polyprotein processing and is active in a dimeric form.

Our efforts to design novel a-ketoamides as broad-spectrum inhibitors of coronavirus M pro s and enterovirus 3C pro s started with a detailed analysis of the following crystal structures of unliganded target enzymes. PDB entries 1UJ1 2BX3 2BX4. Broad-spectrum inhibitors against 3C-like proteases of feline coronaviruses and feline caliciviruses.

Here we show the prodrug and. GC376 is a broad-spectrum antiviral medication under development by the biopharmaceutical company Anivive Lifesciences for therapeutic uses in humans and animals. One possible way to address this challenge is to try to design a broad-spectrum inhibitor targeted against the progenitor bat coronavirus such as the one shown here from PDB entry 4yoi which may then provide a head-start for discovering inhibitors against newly emerging viruses.

Bat coronavirus HKU4 M pro as a surrogate for the closely related MERS-CoV protease our unpublished work Ma Xiao et al. These facts call for the development of broad-spectrum anti-coronavirus drugs targeting a conserved target site. Here we evaluated the therapeutic efficacy of our 3CLpro inhibitor in laboratory cats with FIP.